Cotton, M

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ART TOXICITYBMTHf SOUTHfRN AFRICAN JOURNAL Of HIV MfOICINfIncidence rateAdverse reaction No. (lOO' patient-years)Bone marrow 6 6.6Renal stones 5 5.5Bevated AST/ALT 4 4.4Rash 4 4.4lipodystrophy 2 2.2Dyslipidosis 2 2.2Heart 2 2.2Neuropathy 2 2.2Pancreatitis 2 2.2Diarrhoea 1 1.1importance of this observation is that the adverse drugreaction (ADR) profile may be different in South Africa,perhaps due to a more severe disease profile.ADRs were graded from 1 (mild) through 4 (severe)according to a World Health Organisation [WHO)classification. ADRs were experienced by 190 children,representing 39.3% of the total. There were 289 reactions,of which 42 were grade 3 or 4 (14.5%). The grade 3 and 4ADRs are shown in Table I. Two persistently reportedadverse reactions were diarrhoea and raised creatinine.There was only 1 death attributed to the ARVmedication.Fig. 2. Number and percentage of four most common adversedrug reactions in the Italian Collaborative Multicentric Study(BM ~ bone marrOw toxicity).TABLE I. GRADE 3 AND 4 ADVERSE EVENTS SEEN IN HIV-PDsmVE CHILDREN IN THE ITAUAN COUABORATlVEMUlTICENTRIC STUDYThe four most common ADRs are shown in Rg. 2. They werelipid abnormalities (20%), bone marrow toxicity, liverfunction abnormalities (elevated aspartate aminotrans-ferase/alanine aminotransferase (AST/ALn and skin rashes60 o Class50 .' 602 sa40 !!I 34Q%30 30202010'0 0lipid0N A B CThere are two ways in which children may be exposed toARVs. One is in utero or postnatal exposure as a result ofvertical transmission prophylaxis (VrP), and the other istreatment for symptomatic HIV infection.Fig. 7. Disease profile ofHN-positivechildren in the ItalianCollaborative Multicentric Study.Antiretroviral (ARV) toxicity is an important issue that mustbe fully appreciated by prescribing doctors. While thebenefits of therapy are well documented, toxicity is ofconcern and may be extremely serious, occasionallyresulting in fatality. However, most side-effects are notserious and are reversible.SYMPTOMATIC INFECTIONCastelli-Gattinara etal.' presented a comprehensive reviewof ARV toxicity at the XIV International AIDS Congress inBarcelona in July 2002. As this is, to my knowledge, thelargest review of ART toxicity in children, it is worth closeattention. The Italian Multicentric Collaborative Study' wasconducted between 1998 and 2000 and included 29institutions.Mark Cotton, FCPaed (SA)Head, Paedi.auic Infecriow Disun~ ClinU:al and Research Unit, Uniuersiry of SuJ1enbosch and rygerbng Children)- Hospital,1Y~, WCapeANTIRETROVIRAl TOXICITY IN CHILDRENFour hundred and eighty-four patients were enrolled in thestudy (male/female ratio 0.9). The median age was 6.4 years(range 1 month - 18 years). The median follow-up was 709days, but again there was a wide range (8 - 1 381 days).The clinical and immunological profile (Rg. 1) suggestedless severe disease than is commonly seen in South Africa.In the Italian group 71% of patients were eitherasymptomatic (N) or mildly symptomatic (A). In contrast,68% of children first presenting at the Tygerberg FamilyClinic are either stage B (moderate) or C (severe). TheOCTOllfR 2002 -----------1< 1(010). Less frequent side-effects were renal stones,lipodystrophy and gastrointestinal disturbances, includingnausea and vomiting INNl.Lipodystrophy and lipid abnormalities were more commonin children over 10 years of age, and there was a marginallyhigher incidence in females. This observation is ofimportance as these abnormalities, currently rare inchildren in South Africa, will become more important withlonger use of ARVs.Another important observation was that the relative risk ofADRs increased quite significantly when more than threedrugs were used simultaneously (Fig. 3).""108%6420Gt A",h eNSP < 0.05 for all.Fig. 3. Increased relative risk of toxicity when mare than threeantiretraviral drugs are used simultaneously (GI ~gastraintestinal; CNS ~ central nervous system).Many ADRs can be linked to specific ARVs. Examples arelisted in Table 11.The Southern African HIV Clinicians Society's PaediatricDiscussion Group, led by Paediatric Sub-committeeChairman, Dr Leon Levin, was recently informed by OrTABLE 11. SIDE-EFFECTS UNKED TO SPECIFICANTIRETROVIRAL AGENTSDru9 Class Side-effectRitonavir [RlV) PI Unpleasant taste may lead todrug failureZidovudine (ZOV) NRTI Bone marrow suppressionLamivudine NRTI Pancreatitis(3TC),didanosine (ddl)Stavudine [d4D NRTI Peripheral neuritisAll Pis HyperlipidaemiaAbacavir [ABC) NRTI Fatal hypersensitivityreactions: gastrointestinal andrespiratory symptoms, skineruptions, fever and elevatedliver enzymes (AST or ALDNevirapine [NVP) NNRTI Skin rash and hepatotoxicityPI ~ protease inhibitor: NR1l- nucl~der~ transcriprasc inhibitor; NNRTl _ non-nudeosidtr~ tJanscriptase inrobitor.THE SOUTHERN AFRICAN JOURNAL OF HIV MEDICINETammy Meyers that a toddler being treated withdidanosine (ddl) + stavudine (d4n + nevirapine (NVP) haddied of lactic acidosis and hepatic steatosis.VERTICAL TRANSMISSION - THEANTIRETROVIRAL-EXPOSED INFANTIn the antiretroviral-exposed infant mitochondrial toxicitymay occur more frequently than in older children. ARVshave an affinity for mitochondrial gamma-polymerasewhich depletes mitochondrial deoxyribonucleic acid IONA)and causes dysfunction. Mitochondrial dysfunction isgenerally associated with long-term use of NRTls andusually resolves when the drugs are discontinued.In 1999 Blanche et al.' reported on 8 patients withmitochondrial dysfunction following perinatal exposure tothe nucleoside analogues. Four had been exposed tozidovudine (ZOV) alone and 4 to ZOV plus lamivudine. Twoinfants died. These data have not been replicatedelsewhere. For example, no excess mortality was reported infollow-up of infants receiving ZDV after the landmark 076study. In a large database of over 20000 infants and 223infant deaths in several cohorts followed up in the USA, nodeaths suggestive of mitochondrial toxicity were reported.However, the majority of infants were exposed to ZDValone.'In the PETRA trial' involving 1 798 children, the majority ofwhom were exposed to ZDV and lamivudine, there was noexcess mortality. However, a single case of severe transientneonatal lactic acidosis with prophylactic ZDV wasreported in Switzerland by Scalfaro et 0/.' in 1998. Itresolved when the drug was discontinued. This reportsuggests the need for continuing vigilance.In conclusion, ARV toxicity is of concern, especially whenwider access to these drugs is becoming possible. It wouldbe very helpful to have a mechanism for multi-centre datacollection in order to monitor toxicity and efficacy. Thiscould possibly be coordinated through a national bodysuch as the Medical Research Council or a university-baseddepartment of pharmacology.REFERENCESCast~lIi-Gattinar<;s G, Mannino S, Villa M, ~r 01. Italian Multic~ntric CollaborativtStudy. 14th Int~rnational AIDS CongrtsS, Barc~lona, July 2002.~ Blanch~ S, Tardieu M, Rustin P, et al. Mitochondrial dysfunction and ~rinatalexposure to the nucleoside analogues. Lancet 1999; 354: 1084-1089.3 The Perinatal Safety Review Working Group. Nudrosid~ exposure in the children ofHN-infected women receiving antiretroviral drugs: absenc~ of d~f evidenl:e ofmitochondrial disease in children who died under 5 y~ars of ag~ in 5 United Starescchorts. JAcquir Immum:Defic Syndr 2000; 15: 261-268.4. The PETRA study team. Tne efficacy of three short-cou~ r~imffis of zidovudineand lamivudine in pr~nting ~r!y and late transmission of HIV-I from moth~r tochild in Tanzania, South Africa, and Uganda (Petra study}: a randomized, double-blind, placebo--eonuolled trial. LImcer 2002; 359: 1178-1186.5. Scalfaro P, O1essaux J, Buchwalder P, Biollaz J, Micheli JL Severe transient neonaraJlactic acidosis with prophylactic ZDV. Intensive Core Med 1996; 24: 247-250.-----------OCTOBfIl 2002

Antiretroviral toxicity in children

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Antiretroviral toxicity in children

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